Noise-induced hearing loss (NIHL) and age-related hearing loss (AHL or presbycusis) are major health problems. They are common, their consequences are permanent, and their impacts on human communication and quality of life are significant. Although important advances have been made in characterizing the structural changes in the ear that are associated with NIHL or AHL, the mechanisms underlying these changes are poorly understood. In humans, hearing loss secondary to noise exposure is highly variable between individuals: some people have "tough" ears, while others have "tender" ears. In contrast to humans, laboratory mice show significantly less variability in NIHL among individuals within an inbred strain while there are striking differences in NIHL sensitivity between different inbred strains. Our long-term goal is to exploit these strain differences in mouse models to study the genetic factors influencing resistance and susceptibility to NIHL Here we propose to focus on the remarkable NIHL resistance observed in the inbred mouse strain 12986/SvEvTac (129S6). We will address the following Specific Aims: SA 1. Refine and confirm our preliminary Quantitative Trait Locus (QTL) map for NIHL resistance in 129S6. Develop a second NIHL-resistance QTL map in a different mouse strain, MOLF/Ei for comparison. SA 2: Generate congenic strains using both phenotype-driven selection for NIHL resistance and genotype-driven, marker-assisted selection for QTL regions. Isolated QTL regions will be tested for epistatic interactions. SA 3. Identify candidate NIHL resistance genes using DNA microarrays to study changes in gene expression after noise exposure. Genes differentially regulated between strains and mapping within QTL regions will be sequenced in both strains and compared for variations. SA 4. Strong candidate genes will be tested in genetic crosses to determine whether they interact functionally with the NIHL-resistant QTL. Nucleotide differences in genes suspected to account for the QTL will be tested using gene targeting knock-in techniques to see if they are sufficient to transfer NIHL resistance to another strain. The characterization of genes influencing NIHL resistance will provide fundamental insight into the cellular and molecular processes underlying noise-induced cochlear damage. In turn, these insights will be key to devising effective strategies to preserve hearing in human populations.